Alicyclic ketone and intermediates for the preparation thereof



United States PatentO ALICYCLIC KETONE AND INTERMEDIATES FOR THEPREPARATION THEREOF .Ioseph Donald Surmatis, Pompton Plains, N. 3.,assignor to Hofimann-La Roche Inc., Nutley, N. L, a corporation of NewJersey No Drawing. Application September 13, 1954, Serial No. 455,763

Claims. (Cl. 260-587) This invention relates to novel chemical compoundshaving utility in the perfume, cosmetic and pharmaceutical industries,for example as odor-imparting agents, and as intermediates forodor-imparting agents and pharmaceuticals; and to novel intermediatesand novel processes useful in preparing said compounds. An importantaspect of the invention relates to the novel compound 4-(6-ethyl-2,6-dimethyl-1-cyclohexenyl)-3-buten-2-one, and to a process ofmaking the same from the known compound 3-methyl-lpenten-3-ol (which canalso be identified as ethyl-rnethyl-vinyl-carbinol). Because of itspleasant fragrance, reminiscent of violets, but with cedar notes,4-(6-ethyl-2,6-dimethyl-l-cyclohexenyl)-3-buten-2-one is useful as anodor-imparting agent in the preparation of perfumes and of scentedcompositions generally.

In one comprehensive embodiment, the invention provides a process forconverting the known starting material 3-methyl-1-penten-3-ol to thenovel butenone derivative identified above, which comprises the steps ofhalogenating the 3-methyl-l-penten-3-ol to produce l-halo-3-methyl-Z-pentene, condensing the latter with an acetoacetic acid esterand subjecting the condensation product to ketonic scission to produce6-methyl-5-octen-2-one, condensing the latter with acetylene to produce3,7-dimethyl-6-nonen-l-yn-3-ol, hydrogenating the latter to produce3,7-dimethyl-1,6-nonadien-3-ol, oxidizing the latter to produce3,7-dimethyl-2,6-nonadien-l-al, condensing the latter with acetone toproduce 6,l0-dimethyl-3,5,9- dodecatrien-Z-one and cyclizing the latterto produce 4- (6-ethyl-2,6-dimethyll-cyclohexenyl) -3 -buten-2-0ne.

A preferred method of executing this aspect of the invention comprisesthe steps of: reacting 3-methyl-1-penten-3-0l with a concentratedaqueous solution of a hydrohalic acid (such as commercial concentratedhydrochloric acid or commercial concentrated hydrobromic acid) therebyproducing the corresponding 1-halo-3-methyl-2- pentene; condensing thelatter with a lower alkyl acetoacetate (such as ethyl acetoacetate) inthe presence of an alkali metal condensation agent (such as sodium) oralternatively in the presence of a corresponding alkali metal alkoxide(such as sodium methoxide) and decarboxylating the resultingcondensation product (for example, by saponifying with an alkali metalhydroxide and subsequently acidifying) thereby producing6-methyl-S-octen- Z-one; condensing the latter with acetylene (forexample, by reacting with acetylene in liquid ammonia in the presence ofan alkali metal condensation agent) thereby producing3,7-dimethyl-6-nonen-1-yn-3-ol; partially hydrogenating the latter (forexample, by reducing with elemental hydrogen in the presence of ahydrogenation catalyst selective to catalyze the hydrogenation of anacetylenic bond preferentially to an olefinic bond) thereby producing3,7-dimethyl-1,6-nonadien-3-ol; oxidizing the latter (for example, bytreating with chromic acid) thereby producing3,7-dimethyl-2,6-nonadien-l-al; condensing the latter with acetone (forexample, by treating with acetone in the presence of a condensationagent such as an alkali metal hydroxide or an aluminum alkoxide) therebypror, 2,815,379 Patented Dec. 3, 1957 ducing6,10-dimethyl-3,5,9-dodecatrien-2-one; and cyclizing the latter (forexample, by treating with sulfuric acid) thereby producing4-(6-ethyl-2,6-dimethyl-l-cyclohexenyl) -3-buten-2-one.

The illustrative mode of procedure disclosed above can be traced withreference to the following schematic flow sheet:

FLOW SHEET I 3-methyl-1-penten-3-ol II l-halo-S-methyl-Z-pentene III3-lower-carbalkoxy-6 methyl-5-octen-2-one IV 6-methyl-5-octen-2-one V3,7-dimethyl-6-nonen-1-yn-3-ol VI 3,7-dimethyl-l, 6-nonadien-3-ol VII3,7-dimethyl-2j6-nonadien-l-al VIII J,

6,10-dimethyl-3,5,9-dodecatrien-2-one i IX4-(6-ethyl-2,6-dimethyl-l-cyclohexenyl) -3-buten-2-one Example 1 (I- 11)600 g. of 3-methyl-l-penten-3-ol was cooled to +15 C. with an ice bath,then 1800 cc. of concentrated aqueous hydrochloric acid (37%) was pouredinto the reaction vessel. The mixture was stirred for 30 minutes. Theoil, comprising essentially 1-chloro-3-methyl-2-pentene, was separated,washed three times with 500 cc. of water and dried over calciumchloride.

Example 2 (II III IV) Four liters of benzene, 1040 g. of ethylacetoacetate and 378 g. of sodium methylate were stirred into a 12 literflask. 696 g. of l-choro-3-methyl-2-pentene as produced in Example 1 wasadded from a separatory funnel in 2 hours at 60 C. The stirring was thencontinued at 60 C. overnight.

The mixture was diluted with four liters of water. The oil was separatedand the benzene was distilled off under vacuum. The thick residue,3-carbethoxy-6-methyl-5- octen-Z-one, was placed in a 5 liter flask with2 liters of ethyl alcohol, 1 liter of water and 500 grams of potassiumhydroxide. This was stirred for two hours, then allowed to setovernight, thereby forming the potassium salt of3-carboxy-6-methyl-5-octen-2-one.

Concentrated hydrochloric acid was added to the stirred reaction mixturefrom a separatory funnel until strongly acid. The oil layer was removed,and the aqueous portion was extracted with one liter of benzene. Thecombined oils were water washed and fractionated to yield6-methyl-5-octen-2-one, distilling at C./l0 mm.,

n =l.4412. This compound has an odor generally reminiscent of citrusfruit.

Example 3 (IV V) 84 g. of metallic sodium was dissolved in 3 liters ofliquid ammonia. Acetylene was bubbled into the stirred solution untilits color changed from blue to a white. 420 g. of 6-methyl-5-octen-2-onewas dissolved in 500 cc. of diethyl ether and dropped into the stirredreaction mixture in one hour. Stirring was then continued for 3 hourswhile a slow stream of acetylene was bubbled in. The acetylene was thenstopped, but the stirring was continued for about 15 hours. The ammoniawas then distilled off and the residue in the reaction vessel was Washedwith 2 liters of aqueous sulfuric acid. The product was then waterwashed, dried over anhydrous calcium sulfate and fractionated to yield3,7-dimethyl-6-nonen-1- yn-3-ol, distilling at 89 C./ mm., n =1.46l2.This compound has an odor generally reminiscent of bergamot.

Example 4 (V-+ VI) 300 g. of 3,7-dimethyl-6-nonen-1-yn-3-ol, 30 g. of 5%lead-palladium-calcium carbonate catalyst [Lindlar, Helvetica ChimicaActa 35, 446 (1952)] and 300 cc. of petroleum ether were placed in aflask provided with a stirrer and hydrogenated at 2530 C. at oneatmosphere hydrogen pressure until 1.9 mols of hydrogen were consumed.Fractionation of the product gave 3,7-din1ethyl- 1,6-nonadien-3-oldistilling at 132 C./ 86 mm., n =1.4603. This compound has an odorgenerally reminiscent of citrus fruit.

Example 5 (VI-e VII) In a fiask fitted with a stirrer, thermometer,dropping funnel, and a cold water bath, were placed 1500 cc. of water,250 g. of sodium dichromate, 125 cc. of glacial acetic acid, 200 cc. ofbenzene, and 125 g. of 3,7-dimethyl- 1,6-nonadien-3-ol. To the stirredreaction mixture was added a solution of 125 cc. of concentratedsulfuric acid in 400 cc. of water over a period of two hours. During theaddition, the temperature was controlled at 40 C. The stirring wascontinued for an additional hour; then one liter of water was added. Theoil layer was removed with a separatory funnel, and the aqueous layerwas extracted with 400 cc. of benzene. The oil and benzene extracts werecombined and Washed until neutral. The oil was distilled through acolumn under vacuum. The product, 3,7-dimethyl-2,6-nonadien-l-al,distilled at 135 137 C./25 mm., n :1,4830. The semicarbazone derivativemelted at 159 C. The 3,7-dimethyl-2,6-nonadien-l-al has an odorreminiscent of lemongrass oil.

Example 6 (VII VIII) 45 g. of 3,7-dimethyl-2,6-nonadien-1-al, 50 g. ofalumi num isopropylate, 600 cc. of acetone and 600 cc. of henzene wereplaced in a 2-liter flask and stirred at reflux temperature for 24hours. The cooled reaction mixture was washed first with dilutehydrochloric acid and finally with water until neutral. The benzene wasdistilled 011?, and the product was fractionated under high vacuum, thedesired product 6,10dimethyl-3,5,9-dodecatrien-2-one being obtained in afraction distilling at 102-103 C./ 0.2

4 mm., n :1.5223. The 2,4-dinitrophenylhydrazone derivative melted at117 C.

Example 7 (VII; VIII, alternate) To a solution of 100 g. of3,7-dimethyl-2,6-nonadicnl-al, 300 g. of acetone and 40 g. of water,there was added, with vigorous stirring, 18 g. of 50% aqueous sodiumhydroxide solution at 16-18 C. The mixture was stirred for 72 hoursunder nitrogen, then neutralized with 20% aqueous sulfuric acid at 5 C.The product was extracted with benzene, water-washed and fractionated.6,10-dimethyl-3,5,9-dodecatrien-Z-one was obtained in a fractiondistilling at 102-103 C./ 0.2 mm.,

The 2,4-dinitrophenylhydrazone needles, M. P. 117 C.

Example 8 (VIII- IX) A solution of 350 g. of concentrated sulfuric acidand g. of glacial acetic acid was cooled to 30 C. g. of6,10-dimethyl-3,5,9-dodecatrien-2-one was added dropwise in 45 minutes,keeping the temperature at --20 to 30 C. The stifi reddish coloredmixture was warmed up to 0 C. and stirred for 10 minutes. This was thenpoured onto 1500 g. of crushed ice. The product was extracted withtoluene, washed with water, then with 20% aqueous sodium hydroxidesolution, and finally with a saturated sodium chloride solutioncontaining a few drops of acetic acid. On fractionation, 4-(6-ethyl-2,6-dimethyl-I-cyclohexenyl)-3-butcn-2-one was obtained in a fractiondistilling at 86.5-87.0" C./0.3 mm., n =1.5165. This compound has anodor reminiscent of violets, but with cedar notes. The2,4-dinitrophenylhydrazone melted at 126 C.

I claim:

1. 6-methyl-5-octen-2-one.

2. 3,7-dimethyl-6-nonen-1-yn-3-ol.

3. 3,7-dimethy1-1,6-nonadien-3-ol.

4. 3,7-dimethyl-2,6-nonadien-l-al.

5. 4 (6 ethyl 2,6 dimethyl 1 -cyclohexeny1)- 3-buten-2-one.

crystallized as red References Cited in the file of this patent UNITEDSTATES PATENTS 2,333,216 Tn'eschmann et a1 Nov. 2, 1943 2,589,275 NavesMar. 18, 1952 2,606,930 Heilbron et a1. Aug. 12, 1952 FOREIGN PATENTS665,147 Great Britain J an. 16, 1952 OTHER REFERENCES Fieser et a1.:Organic Chemistry, 1944, pp. 314 and 987.

Simonsen et al.: The Terpcnes, vol. I, 2nd ed., p. 61 (1947).

Moncrieff: The Chemish'y of Perfumery Materials, p. 99 (1949).

West et al.: Synthetic Perfumes, p. 176 (1949).

Simonsen et al.: The Terpenes, vol. III, pp. 497-498 (1951).

Sondheimer: I. Am. Chem. Soc., vol. 74, pp. 4040- 4043 (1952).

5. 4-(6-ETHYL-2,6-DIMETHYL-L-CYCLOHEXENYL)3-BUTEN-2-ONE.